Twelve to twenty-two percent of all pregnancies end in spontaneous abortion, or miscarriage. Most data available suggest genetic, hormonal or immunological factors associated with a majority of spontaneous abortions. About 40% of all miscarriages are estimated to be the result of chromosomal abnormalities. Various hypotheses have been proposed for the remaining 60%, and a variety of tests and therapies have been proposed for diagnosing and treating high-risk pregnancy. For example, high-risk pregnancies are evaluated using Doppler evaluation of uterine artery blood flow (Caforio, L. et al., Fetal Diagn. Ther. (1999) 14: 201–5), screening for and measurement of anti-paternal antibodies (Orgad, S., et al. Hum. Reprod. (1999) December 14: 2974–9), and measurement of MSAFP (maternal serum alpha-fetoprotein) levels, among others.
Despite the application of currently available technologies for screening high-risk pregnancies, reliable methods have not been found. The pathology of spontaneous abortion is difficult to elucidate. Immunologically, a fetus is a semiallogenic graft and blunting of the immune system is required to permit maintenance of the fetus by the mother. Some have suggested that anti-paternal antibodies cause rejection of the fetus by the maternal immune system, and one treatment that has been proposed for recurrent miscarriage is intravenous immunoglobulin therapy (Daya, S., et al., Hum. Reprod. Update (1999) 5: 475–82). Others have suggested that maternal blood flow to the placenta contributes to spontaneous abortion pathology.
One hypothesis that has been suggested for spontaneous abortion pathology is maternal rejection of the fetus due to complement regulatory proteins at the feto-maternal interface. Although one group has recently described a cell surface protein in mice that is directly involved in fetal survival (Xu, et al., Science (2000) 287:498–501), no such molecule has been described in humans.
Differential expression of complement regulatory proteins at the feto-maternal interface was investigated in 1992 by Holmes, et al. (Holmes, C. H., et al., Eur. J. Immunol. (1992) 22: 1579–85), who suggested that differential expression might reflect the need for specific functional activities within the placenta, and that these proteins might be involved in pregnancy pathologies (Holmes, C. H., et al. (1992) Baillieres Clin. Obstet. Gynaecol. 6: 439–60). Fenichel et al. investigated complement regulatory proteins on human sperm, unfertilized oocytes, and pre-implantation embryos, concluding that selective expression of complement regulatory proteins associated with a lack of MHC class I antigens might represent an immune protective mechanism for gametes and pre-implantation embryos during their travel through the female genital tract (Fenichel, P., et al., Contracept. Fertil. Sex (1995) 23: 576–80).
Pinpointing the pathologic mechanism and devising an accurate screening technique for high-risk pregnancy has, however, been complicated by the complexity of the human immune and reproductive systems. For example, Imrie et al. suggested that reduction in CD35 (CR1) and CD55 (DAF) reflect increased levels of circulating immune complexes and consequent increased complement activation in pregnancy—an outcome that would appear to put the fetus at risk in normal pregnancy, if complement activation is part of the pathology of spontaneous abortion (Imrie, H. J., et al. J. Reprod. Immunol. (1996) 31: 22114 7). And, although the mouse model has provided valuable insights into mechanisms of immune response, there are fetomaternal tolerance mechanisms that are quite different between humans and mice, making extrapolation from the mouse model to the human system problematic. For example, the Crry gene demonstrated by Xu et al. to determine fetal survival in mice is absent in humans.
While pathologic mechanisms associated with spontaneous abortion remain unclear, there remains a need for a simple and effective screening method for identifying high-risk pregnancies.